Process fok preparing substituted



Patented Feb. 2, 1943 UNITED STATES ATENT OFFICE PROCESS FOR PREPARING SUBSTITUTED GUANAMINES Wilbur Null OI'dham, Old Greenwich, Conn., as signor to American Oyanamid Company, New York, N. Y., a corporation of Maine No Drawing. Application August 30, 1941,

Serial No. 409,138

Claims. (Cl. 260-248) This invention relates to a method of prepar- Example 1 ing guanamines in which at least one of the 4-N-pheny1 acetoguanamine ammo groups of the guanamme ring 18 a. cyclic amine. o oHe In the past certain guanamines have been pre- 5 N l T pared by the reaction of esters of certain simple J; (LNEFCfim acids such as formic acid with the corresponding biguanlde. When, however, it is attempted t N to produce a substituted guanamine in which one 7 parts of sodium were dissolved in 450 parts or both of the amino groups are cyclic amines, l of ethanol- 55 Parts Of Ph b g lanide and the reaction does not proceed with a satisfactory 90 Parts f yl t te Were then added and speed and in acceptable yields except with formic the mixture allowed to stand. Precipitation of esters. the guanamine gan in ten minutes and was According to the present invention, I have Complete in 24 hours producing -N-p y found that if the reaction is carried out in the acfftoguanamine having a melting point of 178 presence of a metal alkoxide, the reaction pro- 1n yieldceeds smoothly, rapidly and greatly improved When the same reaction was carried out withyields are obtained. The cyclic amino group in out any Sodium the y d W s Only even the molecule may be a secondary or tertiary after refluxing for 15 hours.

amine. In the latter case, it may form a part Example 2 of the cyclic ring. Examples of such guanamines are -N-phenyl, tolyl, hydroxyphenyl, 4N'pheny1butymguanamm-e nitrophenyl, aminophenyl, hydroxybiphenyl, morpholino, and the like. N/

Without Wishing to limit the mechanism of 5 the reaction to any particular theory, it is my M belief that the metal alkoxide takes part in the N reaction as a reactant. It is certainly not a 879 Parts of phenyl 'biguamde were dissolved catalyst in the ordinary sense of the word bem mixture? 2900 parts methanol n 114 cause when the amounts of alkoxide are inparts of Sodmm as the alkoxlde, and L050 parts creased up to approximately stoichiometrical of ethyl butymte were After Standing v m l equivalency with the substituted blguanlde and g fi g ggg ii ig ggzfiggfi g gfih z ggi ester, yields and speed of reaction increase. The g not having a melting point of 155l56 C. The amount of alkoxide, however, is not critical and 3 yield bf the 4 N pheny1 butymguanamine was in many cases it is possible to obtain satisfactory about results with somewhat less than stoichiometrical equivalents of the alkoxide. The particular Example 3 metal alkoxide used is not of vital importance, 4-N-phenyl-,H-methoxypropionoguanamine substantially the same results being obtained 40 oom i-oonl with sodium and potassium oxide, ethoxide, aluminum isopropoxide, and the like. For practical purposes, however, it is preferable to use the /C NHCH6 sodium alkoxides because of the lower cost. t .N

e The invention will be described in greater de- 70.8 parts of phenyl biguanide were dissolved tail in conjunction with the following examples, in 0 parts of methanol containing parts of which are representative of typical guanamines sodium, and 88.5 parts of beta-methoxypr pi that can be prepared in accordance with the nate were added. After standing for 2st hours present invention. The parts are by'weight. the 4-N-pheny1 p-methoxypropionoguanamine precipitated and was recrystallized from aqueous ethanol and toluene. A yield of about 39% was obtained of a, product having a melting point of 118 C.

293 parts of phenyl biguanide were dissolved in 640 parts of methanol containing 38 parts of sodium and 306 parts of ethyl propionate were added. After about fifteen hours the l-N-phenyl propionoguanamine precipitated, was recrystallized from toluene and melted at about 157-158 C. The yield was 68.2%.

Example 6 l-N-morpholino benzoguanamine C-C eHs N rim-d CNH N CHa-CH:

40 parts of N-biguanylmo-rpholine hydrochloride were mixed with 34 parts of methyl benzoate, using 10.7 parts of sodium in 200 parts of methanol both as a condensing and neutralizing agent. The sodium chloride formed in the neutraliza- GE -CH2 tion of the N-biguanylmorpholine hydrochloride,

is filtered oil and the filtrate allowed to stand for about a day. Gradual solidification takes place. The small amount of liquid remaining is filtered off, producing about 56 parts of solid which is slurried with 100 parts of boiling water, then cooled to 2025 C. and filtered. The prodduct obtained melts at 142-149; C. and analyzes for l-N-morpholino benzoguanamine.

Example 7 4-N-m0rph01ino hexanoguanamine 40 parts of N-biguanylmorpholine hydrochloride are dissolved in 200 parts of methanol containing 8.5 parts of sodium. 48 parts of methyl caproate are then introduced, and the sodium chloride formed is filtered off, the filtrate being allowed to stand. Crystals form gradually and are removed by filtration and washed with water. The melting point of the 4-N-morpholino hex- CHr-CH:

anoguanamine so obtained is l23 C. The product is soluble in acetone, insoluble in water and can be recrystallized from a mixture of acetone and water giving a product which melts at 124 C. The yield is in excess of 60%.

Example 8 4-N-p-hydroxyphenyl butyroguanamine o-caro Ninety parts of l-para-hydroxyphenyl biguanide hydrochloride and 116 parts of ethyl butyrate are added to a solution of 27 parts of sodium in 300 parts of methanol. The sodium chloride formed is removed by filtration and the reaction mixture is allowed to stand. After 24 hours the precipitated guanamine is filtered oil and treated with dilute hydrochloric acid and then enough potassium carbonate to make the suspension slightly alkaline. The product can be recrystallized from a mixture of methanol and water or from a mixture of acetone and water. The 4-N-p-hydroxyphenyl butyroguanamine melts at 205-206 C. andis isolated in a yield of about 38%.

Example 9 4-N-m-aminophenyl butyroguanamine l-m-Aminophenyl biguanide was prepared by refluxing for three hours a mixture of 108 parts of m-phenylenediamine, 97 parts of concentrated hydrochloricacid, 84 parts of dicyandiamide and 300 parts of water. The resulting solution was evaporated to dryness and extracted with ethanol leaving the biguanide hydrochloride. This salt melted at 197 C. with decomposition and was produced in a yield of about 35%.

65 parts of l-m-aminophenyl biguanide hydrochloride and 66 parts of ethyl butyrate are mixed with 200 parts of methanol containing 13 parts of sodium. After filtering ofi the sodium chloride formed, the reaction mixture is allowed to standseveral days. The precipitated guanamine is then filtered off and recrystallized from ethanol using decolorizing charcoal as a clarifying agent. The 4-N-m-aminophenyl butyroguanamine is isolated in a yield of about 23% and after shrinking at C. melts at 200-205 C with decomposition.

Example 10 l-N-hydroxybiphenyl butyroguanamine C-CSHT l chloride and 19 parts of dicyandiamide are dissolved in 250 parts of water and the solution refluxed for one-half hour. The biguanide hydrochloride is recovered by cooling the solution and filtering off the precipitated solid. The l-hydroxybiphenyl biguanide hydrochloride melts at 195-200 C. and is isolated in about a 58% yield.

30 parts of the sodium derivative of this 1- hydroxybiphenyl biguanide and 35 parts of ethyl butyrate are mixed with 175 parts of methanol containing 2.3 parts of sodium. After standing for several days, the 4-N-hydroxybiphenyl butyroguanamine is filtered oil and suspended in 500 cc. of alcohol. The suspension is first made acid with hydrochloric acid and then alkaline with ammonium hydroxide. After dilution with 1500 parts of Water the guanamine is filtered oil and recovered in a yield of about 60%. l-N- hydroxybiphenyl butyroguanamine can be recrystallized from a mixture of the ethyl ether of ethylene glycol and water and melts at 2170 C.

What I claim is:

1. A method of producing a guanamine in which the 4-carbon atom of the triazine ring is attached by a carbon-to-nitrogen bond to the radical of a cyclic amine and the 6-carbon atom of the triazine ring is attached to a radical of the group consisting of amine, alkyl amines and cyclic amines through a carbon-to-nitrogen bond which comprises reacting a correspondingly substituted biguanide with an ester of a carboxylic acid in the presence of an alkali metal alkoxide.

2. A method of preparing a guanamine in which the 4-carbon atom of the triazine ring is attached by a carbon-to-nitrogen bond to the radical of a cyclic amine which comprises reacting the corresponding l-substituted biguanide with an ester of an organic carboxylic acid in the presence of an alkali metal alkoxide.

3. A method of producing a 4-N-ary1guanamine which comprises reacting the corresponding l-arylbiguanide with an ester of an organic carboxylic acid in the presence of an alkali metal alkoxide.

4. A method of producing a 4-N-phenylgua namine which comprises reacting l-phenylbiguanide with an ester of an organic carboxylic v acid in the presence of an alkali metal alkoxide.

5. A method of producing a 4-N-morpholinoguanamine which comprises reacting l-biguanylmorpholine with an ester of an organic carboxylic acid in the presence of an alkali metal alkoxide.

6. A method according to claim 1 in which the alkoxide is present in approximately stoichiometrical proportions.

'7. A method according to claim 2 in which the alkoxide is present in approximately stoichiometrical proportions.

8. A method according to claim 3 in which the alkoxide is present in approximately stoichiometrical proportions.

9. A method according to claim 4 in which the alkoxide is present in approximately stoichiometrical proportions.

10. A method according to claim 5 in which the alkoxide is present in approximately stoichiometrical proportions.

WIILBUR NULL OLDHAM. 

